Type I interferon (IFN) signal transduction through STAT proteins is the paramount host response to virus infections, and its importance is underscored by the wide variety of strategies that diverse viruses have evolved to evade IFN antiviral systems. The Paramyxovirus family of negative-strand RNA viruses includes a number of well known and emerging human pathogens with significant health consequences. Many Paramyxovirus species have evolved protein inhibitors of IFN induction and IFN signal transduction to bypass host innate antiviral immune responses. One fundamental element of host defenses, STAT protein signal transduction, is a key target for Paramyxovirus host antagonism. A single viral gene product common to many Paramyxovirus genera, the V protein, can disrupt IFN signaling by targeting STAT proteins of the IFN-activated transcription factor ISGF3. We have discovered that diverse V proteins can target STAT signaling, but the mechanisms of interference vary widely between Paramyxovirus genera. As a key element of viral host evasion, the V-STAT interaction is a prime target for antiviral therapeutic intervention. The proposed studies will combine molecular cell biology, biochemistry, and virology methods to provide a greater understanding of the molecular basis of host evasion strategies used by two medically important Paramyxoviruses, measles virus and mumps virus. It is anticipated that investigation of these host evasion strategies will also reveal fundamental principles of cellular antiviral responses, and should also lead to new therapies for the treatment and prevention of these medically important virus infections. Specific aims of this proposal will uncover the molecular composition and determinants of target specificity for differential STAT1 and STAT3 degradation by mumps virus V protein, evaluate the advantages of STAT3 evasion during virus replication, determine the exact biochemical basis for STAT binding to measles virus V protein, and identify measles V-interacting cellular proteins involved in IFN inhibition and STAT nuclear import disruption. PUBLIC HEALTH RELEVANCE: This research will determine the basis for host targeting specificity and decipher the cellular mechanisms underlying immune evasion by mumps virus and measles virus, two significant pathogens that are worldwide health concerns and have been re-emerging recently in the United States. Furthermore, the principles of host antiviral response and cellular immune regulation uncovered can be applied to human diseases that are characterized by hyperactive cellular signal transduction as well as diverse viral pathogens.